US 9,943,552 B2 · Assignee: DePuy Synthes Products, Inc. · Inventors: Kihm; Anthony J. et al.
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Methods for treating Alzheimer's disease, or the symptoms of Alzheimer's disease, are provided. Some embodiments are to methods for treatment comprising administering cells obtained from human umbilical cord tissue, or administering pharmaceutical compositions comprising such cells or prepared from such cells, such as cell derivatives. Some embodiments are to methods for treatment comprising hUTC. Pharmaceutical compositions for use in the inventive methods, as well as kits for practicing the methods are also provided.
Alzheimer's disease is the most common cause of dementia in North America and Europe. Generally, Alzheimer's disease is a common and complex disorder characterized by adult-onset progressive dementia. The disease usually begins after age 65, and the risk of Alzheimer's disease increases with age. Indeed, approximately 10 percent of all persons over the age of 70 have significant memory loss and more than half of these individuals have Alzheimer's disease. The prevalence of dementia in individuals over the age of 85 is estimated to be about 25-45%. Further, Alzheimer's disease is believed to be the fourth leading cause of death in elderly adults. A record number of people are becoming elderly in the next few decades. Unless effective methods for prevention and treatment are developed by the pharmaceutical and medical industries, Alzheimer's disease may reach epidemic proportions by the mi
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The present invention relates generally to compositions, methods and kits for treating Alzheimer's disease by administration of cells or cell derivatives. In particular, the invention provides administering cells or cell derivatives to a patient to reduce the accumulation of plaque proteins as well as provide support factors to reduce neuronal cell death. The invention also provides administering cells or cell derivatives to a patient to treat symptoms of Alzheimer's disease.
Alzheimer's disease is the most common cause of dementia in North America and Europe. Generally, Alzheimer's disease is a common and complex disorder characterized by adult-onset progressive dementia. The disease usually begins after age 65, and the risk of Alzheimer's disease increases with age. Indeed, approximately 10 percent of all persons over the age of 70 have significant memory loss and more than half of these individuals have Alzheimer's disease. The prevalence of dementia in individuals over the age of 85 is estimated to be about 25-45%. Further, Alzheimer's disease is believed to be the fourth leading cause of death in elderly adults.
A record number of people are becoming elderly in the next few decades. Unless effective methods for prevention and treatment are developed by the pharmaceutical and medical industries, Alzheimer's disease may reach epidemic proportions by the middle of the next century. Because of increasing longevity, the occurrence of Alzheimer's disease in the elderly presents a tremendous medical, economic and social problem facing the health care industry today.
Alzheimer's disease is a degenerative disease of the brain from which there is no recovery. The disease attacks nerve cells in all parts of the cortex of the brain, as well as some of the surrounding structures and tissues. Typically, Alzheimer's disease begins with subtle and poorly recognized failure of memory. The early symptoms of Alzheimer's disease may be overlooked because such symptoms resemble signs of natural aging. These symptoms include forgetfulness, loss of concentration, unexplained weight loss and motor problems, including mild difficulties in walking. In healthy individuals, similar symptoms can result from fatigue, grief or depression, illness, vision or hearing loss, the use of alcohol with certain medications, or simply the inability to remember complex details at one time. Accompanying sensory problems, such as hearing loss and a decline in reading ability, as well as general physical debility indicate a short survival time. Other symptoms include confusion, poor judgment, language disturbance, agitation, withdrawal, and hallucinations. Some patients may develop seizures, Parkinsonian-type features, decreased muscle tone, myoclonus, incontinence and mutism. The patient may also exhibit symptoms such as inability to perform routine tasks, loss of language skills, inability to plan, and personality changes. Over time, these changes become so severe and impairing that the patient loses all memory and mental functioning to the point of complete central nervous system (CNS) collapse and cessation of regulated circulatory and respiratory function.
Clinically, Alzheimer's disease is a neuropathological disease. Recognized clinical signs include progressive dementia and cerebral cortical atrophy, which can be established by neuroimaging studies. In addition, neuropathological findings usually include microscopic A-beta amyloid neuritic plaques, intraneuronal neurofibrillary tangles and amyloid angiopathy. Studies indicate that Alzheimer's disease is associated with cerebral cortical atrophy, histological findings of beta amyloid plaques and findings of intraneuronal neurofibrillary tangles within the cortical regions of the brain.
Neurofibrillary tangles are tangled fibers, which are the damaged remains of microtubules, within the cortical region of the brain, that support the structure allowing the flow of nutrients through nerve cells (neurons). Beta amyloid is an insoluble protein which is a fragment of a larger protein (APP). APP itself appears to be important in nerve protection. Should the enzyme involved in cutting APP into fragments of beta amyloid fail to function, APP has been shown to form sticky patches called neuritic plaques, which decrease neuronal function and signal transmission within the brain. Generally, such neuritic plaques are found on the outside of nerve cells surrounded by debris of dying neurons.
In addition, high levels of beta amyloid are associated with reduced levels of the neurotransmitter acetylcholine. Neurotransmitters are chemical messengers in the brain that transmit various signals, messages, and neurochemical information within the various regions of the CNS. Acetylcholine is part of the cholinergic system, which is essential for memory and learning, and is progressively destroyed in patients suffering from Alzheimer's disease. Thus, it is theorized that beta amyloid in the form of neuritic plaques causes a decrease in the neurotransmitter, acetylcholine, leading to progression of Alzheimer's disease.
Currently, Alzheimer's disease treatment is based on managing disease symptomology for each individual's disease progression. Although there are drugs for treating Alzheimer's disease, there is no cure for the disease. Treatments include drugs that alter neurotransmitter availability in the CNS. For instance, some drugs increase acetylcholine in the brain, such as acetylcholinesterase inhibitors, work as dopamine receptor antagonist, and noncompetitive NMDA receptor antagonists. Other drugs are used to treat the aggression and psychosis of Alzheimer's patients.
Currently available treatments have side effects, including nausea, diarrhea, hepatotoxicity, abdominal cramping, ulcers, gastrointestinal bleeding, orthostatic hypotension, drowsiness, dizziness, sexual dysfunction, and insomnia. At times, the side effects are so severe that the physician ceases treatment.
Given the current limitations in treating Alzheimer's disease, there exists a need for alleviating Alzheimer's disease symptoms in individuals that is cost effective, has minimal potential for side effects, and positively increases memory, cognitive function, and ability to perform daily living activities.
FIG. 1 shows the results of Morris Water Maze testing across all treatment groups for one day in a visible platform test evaluated by swim speed.
FIG. 2 shows the Gallagher Cumulative test scores for all treatment groups of rats treated with PBS or hUTC for hidden platform acquisition over time.
FIG. 3 shows the latency measurements for all treatment groups of rats treated with PBS or hUTC for hidden platform acquisition over time.
FIG. 4 are the Gallagher Cumulative test scores in reverse hidden platform acquisition for all treatment groups of rats treated with PBS or hUTC at days 7-9.
FIG. 5 are the latency measurements in reverse hidden platform acquisition for all treatment groups of rats treated with PBS or hUTC at days 7-9.
The problems presented are solved by the compositions, methods and kits of the illustrative embodiments described herein. These embodiments provide methods for treating Alzheimer's disease, or the symptoms of Alzheimer's disease, by administering a cell, population of cells or cell derivatives. While not wishing to be bound by any mechanism of action, the inventors believe that cells or cell derivatives administered to an Alzheimer's patient reduce the prevalence of the plaque, not only reducing senile plaque progression, but also increasing neuroprotection. Further, the inventors believe that administration of the cell or cell derivatives facilitates plaque removal by a phagocytic mechanism. The present invention is based, at least in part, on the discovery that cells, including stem cells and/or postpartum-derived cells derived from human placental or umbilical cord tissue (“hUTC”), can be administered locally or systemically to a patient with Alzheimer's disease. In particular, the present invention relates to administration of hUTC or hUTC derivatives to patients with Alzheimer's disease.
Specific embodiments of the invention are directed to the treatment of the signs/symptoms of Alzheimer's disease, including forgetfulness, loss of concentration, unexplained weight loss and motor problems, difficulties in walking, hearing loss, decline in reading or linguistic ability, confusion, poor judgment, agitation, withdrawal, hallucinations, seizures, Parkinsonian-type features, decreased muscle tone, myoclonus, incontinence, mutism, inability to perform routine tasks, inability to plan, and personality changes.
In one embodiment, the invention pertains to a method of treating a subject having Alzheimer's disease by administering a population of cells in an amount effective, such that the Alzheimer's disease is treated. In another embodiment, the cells administered are postpartum-derived cells. In some embodiments, the postpartum-derived cells are derived from human placental, and in other embodiments the postpartum-derived cells are derived from umbilical cord tissue. In another embodiment, the cells administered are stem cells. In one embodiment, the cells are hUTC.
In another embodiment, the invention pertains to a method of treating a subject having signs and/or symptoms of Alzheimer's disease by administering a population of cells in an amount effective, such that the signs and/or symptoms of Alzheimer's disease are treated. In another embodiment, the cells administered are postpartum-derived cells. In some embodiments, the postpartum-derived cells are derived from human placental, and in other embodiments the postpartum-derived cells are derived from umbilical cord tissue. In another embodiment, the cells administered are stem cells. In one embodiment, the cells are hUTC.
In some embodiments, the population of cells is administered in a single injection. In other embodiments, the population of cells is administered in more than one injection. In one embodiment, the cells are administered to the CNS via cerebral spinal fluid (CSF). In another embodiment, the cells are administered locally to the CNS at the area of plaque formation. In another embodiment, the cells are administered locally to a region of brain involved in memory and learning, including but not limited to, amygdale, striatum, mammillary bodies such as the hippocampus and diencephalons, temporal cortex, thalamus, hypothalamus, peripheral cortex, and neocortex.
The administration site may be any that is determined by the medical professional to be best effective, and thus may be at, proximal, or distal to the site of plaque formation.
The cell administration may be by any means, including but not limited to, into the CSF, cerebral tissue, and the like. The delivery may also occur by syringes with needles and/or catheters with or without pump devices. The delivery may include use of pharmaceutically acceptable carriers such as saline, collagen, cross-linked collagen, hyaluronic acid, synthetic polymer based systems, liquids, hydrogels, or scaffolds. In addition, some embodiments include use of one or more growth factors injected in parallel, sequentially, or formulated directly into one or more pharmaceutically acceptable carriers.
In some embodiments, the population of cells is administered with at least one other agent, including but not limited to, selected extracellular matrix components, microcarriers, microparticulate systems including anti-apoptotic agents, anti-inflammatory compounds, immunosuppressive or immunomodulatory agents, anti-oxidants, and other factors to enhance cell survival, proliferation and other cell functions. In one embodiment, the composition further comprises at least one of the agents or factors selected from the group consisting of neurotrophic factors.
In some embodiments, the cells are pre-treated with electrical stimulation prior to administration.
In other embodiments, the cells are modified to express one or more genes that enhance neural cell survival, differentiation or phagocytic activity of the cells.
In all embodiments, cell derivatives such as lysate or conditioned media, may be co-administered with, or administered instead of, the instant population of cells.
Other embodiments of the invention feature compositions and kits for treating a patient with Alzheimer's disease comprising at least a population of cells and a pharmaceutically acceptable carrier. Other composition and kit embodiments may include other agents, growth factors, and compounds such as anti-apoptotic agents, anti-inflammatory compounds, immunosuppressive or immunomodulatory agents, anti-oxidants, and other factors to enhance cell survival, proliferation and other cell functions. The pharmaceutical compositions and kits are designed and/or formulated for practicing the methods of the invention as outlined above and below.
Other objects, features, and advantages of the illustrative embodiments will become apparent with reference to the drawings and detailed description that follow.
In the following detailed description of the illustrative embodiments, reference is made to the accompanying drawings that form a part hereof. These embodiments are described in sufficient detail to enable those skilled in the art to practice the invention, and it is understood that other embodiments may be utilized and that logical structural, mechanical, electrical, and chemical changes may be made without departing from the spirit or scope of the invention. To avoid detail not necessary to enable those skilled in the art to practice the embodiments described herein, the description may omit certain information known to those skilled in the art. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope of the illustrative embodiments are defined only by the appended claims.
To better clarify the invention, the following definitions are provided.
The terms “plaque site,” “neuritic plaque,” “neural injury” and “site of neural damage” as used herein are interchangable and generally refer to an area of the central nervous system where amyloid plaques have accumulated on or adjacent to neural tissue of an individual, and may include but not limited to, connective tissue and vascular tissue. The terms may further refer to areas of any tissue that are not necessarily wounded or defected, but are instead areas in which it is desired to reduce growth of plaques. The term may also refer to nervous tissue that while having no apparent plaque formation, clinical observations, prior research or current individual patient's indicate the presence of an abnormality in neural tissue function, as observed by alternations in memory, learning, motor function, audiovisual function, linguistics function, and the like.
The terms “individual,” “patient” or “subject” as used herein generally refer to any form of animal, including mammals, such as humans and monkeys, who are treated with the pharmaceutical or therapeutic compositions or in accordance with the methods described. The term “xenogeneic” as used herein refers to administration or administration of cells from a donor of one species into a subject of a different species.
The terms “treat,” “treating” or “treatment” as used herein generally refer to amelioration or reduction in any symptom of Alzheimer's disease, reduction in plaque formation, and diminishing of plaques, for a period of time following administration of a population of cells into a subject suffering from Alzheimer's disease. The amelioration or reduction also includes any objective or subjective parameter such as abatement, remission, diminishing of symptoms or making the Alzheimer's disease more tolerable to the patient, slowing in the rate of degeneration or decline, making the final point of degeneration less debilitating, improving a subject's physical or mental well-being, or prolonging the length of survival. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination or neurological examination
The terms “effective period,” “effective period of time” or “effective conditions” refer generally to a period of time or other controllable conditions (e.g., temperature, humidity for in vitro methods), necessary or preferred for an agent or pharmaceutical composition to achieve its intended result.
The term “effective amount” as used herein generally refers to a concentration or amount of a compound, material, or composition, as described herein, that is effective to achieve a particular biological result. Such results include, but are not limited to, the improvement of, and/or decrease in symptoms of, Alzheimer's disease for a patient. Such effective activity may be achieved, for example, by administering the cells and/or compositions of the present invention to patients with Alzheimer's disease. With respect to the population of cells as administered to a patient, an effective amount may range from 300,000 to 2 million cell/kg local administration and 0.16 million cell/kg-10 million cell/kg when delivered systemically. It is appreciated that the number of cells administered will vary depending on the specifics of the area of treatment, including but not limited to, the size or total volume/surface area to be treated, and proximity of the site of administration to the location of the region to be treated, method of delivery, i.e., such as delivery to the CSF versus intra-neural treatment, and the like.
The term “stem cell” as used herein generally refers to undifferentiated cells defined by the ability of a single cell both to self-renew, and to differentiate to produce progeny cells, including self-renewing progenitors, non-renewing progenitors, and terminally differentiated cells. Stem cells are also characterized by their ability to differentiate in vitro into functional cells of various cell lineages from multiple germ layers (endoderm, mesoderm and ectoderm), as well as to give rise to tissues of multiple germ layers following administration, and to contribute substantially to most, if not all, tissues following injection into blastocysts. The stem cells may come from any source, including but not limited to, embryonic and fetal sources, postpartum tissues such as the umbilical cord and placenta, and adipose cells. Stem cells can be classified according to their developmental potential as totipotent, pluripotent, multipotent, oligopotent and unipotent. Stem cells can also be categorized based on the source from which they are obtained, and include adult stem cells, embryonic stem cells, fetal stem cells and postpartum stem cells.
As used here, the term “embryonic tissue” generally refers to a tissue originating from the embryo (which in humans refers to the period from fertilization to about six weeks of development). Further the term “fetal tissue” refers to tissue originating from the fetus, which in humans refers to the period from about six weeks of development to parturition and “extraembryonic tissue” refers to tissue associated with, but not originating from, the embryo or fetus. Extraembryonic tissues include extraembryonic membranes (chorion, amnion, yolk sac and allantois), umbilical cord and placenta (which itself forms from the chorion and the maternal decidua basalis).
As used herein the phrase “neural cell” includes both nerve cells (i.e., neurons, e.g., uni-, bi-, or multipolar neurons) and their precursors and glial cells (e.g., macroglia such as oligodendrocytes, Schwann cells, and astrocytes, or microglia) and their precursors.
The term “progenitor cell” as used herein generally refers to a cell with the capacity to create progeny that are more differentiated than it, and yet retains the capacity to replenish the pool of progenitors. By that definition, stem cells themselves are also progenitor cells, as are the more immediate precursors to terminally differentiated cells. When referring to the cells of the present invention, as described in greater detail below, this broad definition of “progenitor cells” may be used. In a narrower sense, a progenitor cell is often defined as a cell that is intermediate in the differentiation pathway, i.e., it arises from a stem cell and is intermediate in the production of a mature cell type or subset of cell types. This type of progenitor cell is generally not able to self-renew. Accordingly, if this type of cell is referred to herein, it will be referred to as a “non-renewing progenitor cell” or as an “intermediate progenitor or precursor cell.”
As used herein, the phrase “differentiation” generally means the process by which an unspecialized (“uncommitted”) or less specialized cell acquires the features of a specialized cell, such as a nerve cell or a muscle cell, for example. A differentiated cell is one that has taken on a more specialized (“committed”) position within the lineage of a cell. The term committed, when applied to the process of differentiation, refers to a cell that has proceeded in the differentiation pathway to a point where, under normal circumstances, it will continue to differentiate into a specific cell type or subset of cell types, and cannot, under normal circumstances, differentiate into a different cell type or revert to a less differentiated cell type. De-differentiation refers to the process by which a cell reverts to a less specialized (or committed) position within the lineage of a cell. As used herein, the lineage of a cell defines the heredity of the cell, i.e. which cells it came from and what cells it can give rise to. The lineage of a cell places the cell within a hereditary scheme of development and differentiation.
The cells used in the present invention may include what is termed “postpartum cells” or “postpartum-derived cells.” These cells may be umbilicus-derived cells or placenta-derived cells. In addition, the cells may be described as being stem or progenitor cells, the latter term being used in the broad sense. The term “derived” is used to indicate that the cells have been obtained from their biological source and grown or otherwise manipulated in vitro (e.g., cultured in a growth medium to expand the population and/or to produce a cell line). The in vitro manipulations of umbilical stem cells and the unique features of the umbilicus-derived cells of the present invention are described in detail below. Further, “hUTC” as used herein generally refers to human umbilical cord derived cells, and is the same as human umbilical tissue derived cells.
A “population” or “population of cells” generally refers to two or more cells. A population of cells can be obtained from the same or different source(s), e.g., the same donor or several different donors. Moreover, the cells in a population are not necessarily of the same cell type. A population of cells can include a mixture of, for example, both umbilical-derived and placenta-derived cells.
The term “isolate” as used herein generally refers to a cell which has been separated from its natural environment. This term includes gross physical separation from its natural environment, e.g., removal from the donor animal. In preferred embodiments, an isolated cell is not present in a tissue, i.e., the cell is separated or dissociated from the neighboring cells with which it is normally in contact. Preferably, cells are administered as a cell suspension. As used herein, the phrase “cell suspension” includes cells which have been dissociated, e.g., by subjecting a piece of tissue to gentle tritration, which are in contact with a medium.
As used herein, the term “growth medium” generally refers to a medium sufficient for the culturing of postpartum-derived cells. In particular, one medium for the culturing of the cells of the invention comprises Dulbecco's Modified Essential Media (DMEM). Particularly preferred is DMEM-low glucose (DMEM-LG) (Invitrogen, Carlsbad, Calif.). The DMEM-LG is preferably supplemented with serum, most preferably fetal bovine serum or human serum. Typically, 15% (v/v) fetal bovine serum (e.g. defined fetal bovine serum, Hyclone, Logan Utah) is added, along with antibiotics/antimycotics (preferably 100 Unit/milliliter penicillin, 100 milligrams/milliliter streptomycin, and 0.25 microgram/milliliter amphotericin B; Invitrogen, Carlsbad, Calif.), and 0.001% (v/v) 2-mercaptoethanol (Sigma, St. Louis Mo.). In some cases different growth media are used, or different supplementations are provided, and these are normally indicated in the text as supplementations to growth medium. In certain chemically-defined media the cells may be grown without serum present at all. In such cases, the cells may require certain growth factors, which can be added to the medium to support and sustain the cells. Presently preferred factors to be added for growth on serum-free media include one or more of bFGF, EGF, IGF-I, and PDGF. In more preferred embodiments, two, three or all four of the factors are add to serum free or chemically defined media. In other embodiments, LIF is added to serum-free medium to support or improve growth of the cells.
A “cell derivative” refers to conditioned medium or cell lysate.
A “conditioned medium” is a medium in which a specific cell or population of cells has been cultured, and then removed. When cells are cultured in a medium, they may secrete cellular factors that can provide trophic support to other cells. Such trophic factors include, but are not limited to hormones, cytokines, extracellular matrix (ECM), proteins, vesicles, antibodies, and granules. The medium containing the cellular factors is the conditioned medium.
The term “primary cell culture” is a culture of cells, tissues, or organs taken directly from an organism(s) before the first subculture.
The term “cell line” generally refers to a population of cells formed by one or more subcultivations of a primary cell culture. Each round of subculturing is referred to as a passage. When cells are subcultured, they are referred to as having been “passaged.” A specific population of cells, or a cell line, is sometimes referred to or characterized by the number of times it has been passaged. For example, a cultured cell population that has been passaged ten times may be referred to as a P10 culture. The primary culture, i.e., the first culture following the isolation of cells from tissue, is designated P0. Following the first subculture, the cells are described as a secondary culture (P1 or passage 1). After the second subculture, the cells become a tertiary culture (P2 or passage 2), and so on. It will be understood by those of skill in the art that there may be many population doublings during the period of passaging; therefore, the number of population doublings of a culture may be greater than the passage number. The expansion of cells (i.e., the number of population doublings) during the period between passaging depends on many factors, including but not limited to the seeding density, substrate, medium, growth conditions, and time between passaging.
The terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable medium” as used herein generally refers to reagents, cells, compounds, materials, compositions, and/or dosage forms that are not only compatible with the cells and other agents to be administered therapeutically, but also are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other complication commensurate with a reasonable benefit/risk ratio.
As described in greater detail herein, pharmaceutically acceptable carriers suitable for use in the present invention include liquids, semi-solid (e.g., gels) and solid materials (e.g., cell scaffolds and matrices, tubes sheets and other such materials as known in the art and described in greater detail herein). These semi-solid and solid materials may be designed to resist degradation within the body (non-biodegradable) or they may be designed to degrade within the body (biodegradable, bioerodable). A biodegradable material may further be bioresorbable or bioabsorbable, i.e., it may be dissolved and absorbed into bodily fluids (water-soluble implants are one example), or degraded and ultimately eliminated from the body, either by conversion into other materials or breakdown and elimination through natural pathways. The biodegradation rate can vary according to the desired release rate once implanted in the body.
The term “matrix” as used herein generally refers to a mixture of biodegradable and/or bioresorbable materials that are administrated with the cells to a patient. In one embodiment, the matrix provides for sustained release of neurotrophic factors or other agents used in conjunction with the cells and may provide a structure for developing tissue growth in the patient. In other embodiments, the matrix simply provides a temporary scaffold for the developing tissue. The matrix can be in particulate form (macroparticles greater than 10 microns in diameter or microparticles less than 10 microns in diameter), or can be in the form of a structurally stable, three-dimensional implant (e.g., a scaffold). The matrix can be a slurry or hydrogel, or alternatively, can be a three dimensional structure.
The term “scaffold” as used herein generally refers to a three dimensional porous structure that provides a template for cell growth. A scaffold is made of biodegradable and/or bioresorbable materials that degrade over time within the body. The length of time taken for the scaffold to degrade may depend upon the molecular weight of the materials. Thus, higher molecular weight material may result in polymer scaffold which retain their structural integrity for longer periods of time; while lower molecular weights result in both slower release and shorter scaffold lives. The scaffold may be made by any means known in the art. Examples of polymers which can be used to form the scaffold include natural and synthetic polymers. In some embodiments of the invention, the scaffold may be infused with, coated with, or comprised of a population of cells, growth factors, or other nutrients to promote cell growth. In some preferred embodiments, the scaffold contains growth inducing agents including neurotrophins. Further, the growth inducing agents may be synthetic or naturally produced, and may be a fragment, derivative or analog of a growth inducing agent.
“Neurotrophic factor” or “trophic factor” is defined as a substance that promotes survival, growth, proliferation and/or maturation of a cell, or stimulates increased activity of a cell.
For all embodiments of the invention, an individual diagnosed with Alzheimer's disease, or exhibiting symptoms of Alzheimer's disease, is administered a population of cells in an amount effective to treat the Alzheimer's disease, or its symptoms. Specific embodiments of the invention are directed to local administration of a population of cells to facilitate plaque removal by phagocytic mechanisms and/or active endogenous mechanisms to reduce the progression of plaque formation, and stimulate and support neural tissue growth and/or healing. The cells may be any discussed below, including stem cells, postpartum-derived cells, umbilical-derived or placenta-derived cells. In one embodiment, the cells are hUTC. A more detailed explanation of preferred cells is described in the below specification. Some embodiments are to compositions administered to the individual, where the composition includes a population of cells, and a pharmaceutically acceptable carrier. Such compositions can be used in kits for making, using, and practicing such methods and pharmaceutical compositions as described and exemplified herein. The kits can further contain devices to help facilitate administration of the population of cells, such as, for example, needles, tubes, micropipette, and the like. In one embodiment, the kit comprises at least one population of cells, a construct, and an injection device. Further, in some embodiments, the kits can also be coupled with imaging devices that indicate the exact placement of the cells.
In one embodiment, the population of cells is administered to an individual diagnosed with Alzheimer's disease, where the administration is to an area of known plaque formation in the CNS. The Alzheimer's disease may be diagnosed by any means known in the art, including measurement of amyloid beta and tau, or its precursors, fragments, or metabolic compounds in CSF. Alzheimer's may also be diagnosed by measurement of isoprosanes in the individual's fluids, including urine and blood. Other diagnostic methods may include use of brain imaging techniques, for example, magnetic resonance imaging (MRI) to examine brain atrophy, positron emission topography (PET) to image the plaques and tangles of Alzheimer's Disease, and functional MRI (fMRI) to measure oxygen levels in the blood in the hippocampus or other memory and/or learning areas of the brain.
The exact type of cells that make up the population of cells administered is dependent upon the discretion of the medical professional. In one embodiment, the cells administered are postpartum-derived cells. In some embodiments, the postpartum-derived cells are derived from human placental tissue, and in other embodiments the postpartum-derived cells are derived from umbilical cord tissue. In another embodiment, the cells administered are stem cells. In one preferred embodiment, the cells are hUTC. A detailed description of the types of cells suitable for this invention is described below.
The population of cells may administered at, proximal, or distal to an area of the brain where plaques have accumulated on, or adjacent to, neural tissue of an individual. Such areas of the brain may include any involved in memory and learning, including but not limited to, amygdale, straitum, mammillary bodies such as the hippocampus and diencephalons, temporal cortex, thalamus, hypothalamus, peripheral cortex, and neocortex. The exact administration site may be any that is determined by the medical professional to be best effective. In another embodiment, the population of cells is administered directly to the CSF.
The cell administration may be administered by any means determined by the medical professional to be most effective, and can include use of a catheter, syringe, shunt, stent, microcatheter, pump, implantation with a device, or implantation with a scaffold. Further, the cell administration may be by intranasal delivery, intravascular delivery, intracerebral injection and intraventricular injection. In one embodiment, the population of cells may only be administered in only one injection. In some embodiments, the population of cells is administered more in more than one injection. In yet another embodiment, a pump is used to ensure slow, continuous administration of the population of cells.
Pharmaceutical compositions comprising the population of cells can be formulated as liquids, semisolids (e.g., gels) or solids (e.g., matrices, scaffolds and the like). Liquid compositions are formulated for administration by any acceptable route known in the art to achieve delivery of the population of cells to the target neural tissues. Typically, these include injection or infusion, either in a diffuse fashion, or targeted to the site of neurotic plaque formation. For instance, in one embodiment, the population of cells is administered by direct stereotaxic injection, e.g., needle. The needle may be any size to facilitate movement of cells through the hollow bore. The needle may be inserted directly through a bore in the skull, through the neural tissue of the brain to the neural site of interest, or alternatively the needle may be used with a device to ease guidance of the needle to the tissue site, such as, for example, a guide wire. The needle and guidance device can be either preassembled or delivered to the trained practitioner, the trained practitioner may assemble the device himself just prior to or during use.
In an alternate embodiment, a delivery catheter may be used to deliver the population of cells can be inserted into a delivery device which facilitates introduction by e.g., injection, of the cells into the subjects. Such delivery devices include tubes, e.g., catheters, for injecting cells and fluids into the body of a recipient subject. In one embodiment, the cells of the invention can be introduced into the subject at a desired location using a micropipette. The cells of the invention can be inserted into such a delivery device, e.g., a micropipette or syringe, in the form of a solution, e.g., a cell suspension. In addition, the cells of the invention can be administered in a guidance channel (e.g., polyacrylonitrile/polyvinylchloride (PAN/PVC) guidance channels), such as those described in Bunge et al., J Neurology, 1994; 241: S19-S21.
The population of cells or compositions and/or matrices comprising the cells may be delivered to the site via a micro catheter, intracatheterization, or via a mini-pump. The vehicle excipient or carrier can be any of those known to be pharmaceutically acceptable for administration to a patient, particularly locally at the site at which cellular differentiation is to be induced.
Conditioned Media and Cell Lysates
In one embodiment, conditioned media is administered to the individual in addition to, or instead of cells. In another embodiment, cell lysate is administered to the individual in addition to, or instead of cells. In yet another embodiment, conditioned media and cell lysate are administered to the individual in addition to, or instead of cells.
Conditioned medium from cultured PPDCs may be used in vitro and in vivo. Use of the PPDC or other conditioned medium may allow the beneficial trophic factors secreted by the PPDCs to be used allogeneically in a patient without introducing intact cells that could trigger rejection, or other adverse immunological responses. Conditioned medium is prepared by culturing cells in a culture medium, then removing the cells from the medium.
Conditioned medium prepared from population of postpartum-derived cells may be used as is, further concentrated, for example, by ultrafiltration or lyophilization, or even dried, partially purified, combined with pharmaceutically-acceptable carriers or diluents as are known in the art, or combined with other compounds such as biologicals, for example pharmaceutically useful protein compositions. Conditioned medium may be used in vitro or in vivo, alone or combined with autologous or syngeneic live cells, for example. The conditioned medium, if introduced in vivo, may be introduced locally at a site of treatment, or remotely to provide needed cellular growth or trophic factors to a patient.
According to embodiments of the present invention, a stable and scalable process is provided to manufacture reduced serum hUTC-conditioned media. Briefly, the method includes the culture of hUTC under reduced serum conditions. Subsequently the hUTC are washed and grown in serum-free basal media. After approximately 24 hours, the conditioned media is collected, filtered and concentrated by use of an approximately 5 kDa or similar molecular weight cut-off membrane.
The description continues in the full USPTO document.
About 5,950 words. The USPTO PDF has it with every drawing.
Fees are due 3.5, 7.5 and 11.5 years after grant. This patent expired on April 17, 2026, so the fee marked "not paid" was the one that went unpaid.
hUTC AS THERAPY FOR ALZHEIMER'S DISEASE
Filed Mar 2010 · published Sep 2010hUTC as therapy for Alzheimer's disease
Filed Mar 2010 · granted May 2014hUTC AS THERAPY FOR ALZHEIMER'S DISEASE
Filed Apr 2014 · published Aug 2014hUTC as therapy for Alzheimer's disease
Filed Apr 2014 · granted Apr 2018Earlier publications, parents and continuations. None of them can still be enforced, or this patent would not be listed.
Prior art cited by the examiner or applicant. Useful when you check your own idea for novelty.
Everything on this page comes from the documents linked above.
